Ms. Barton, on behalf of the Director General of Therapeutics Products Directorate, welcomed the scientific advisory panel members. She provided context for the meeting, which was to assist in better informing Canadians about the risks of opioid use, reduce easy access to unnecessary opioids and support better treatment options for patients. This is in accordance with the five-point action plan put forward by the Minister of Health. She explained the process to be used for the meeting, and once again thanked the panel for their time and for providing advice to Health Canada. She then handed the meeting over to the Chair of the panel.

Chair's address (Mitchell Levine)

The Chair asked members and attendees to introduce themselves. Panel members verbally provided a summary of their conflict of interest declaration that had been submitted to Health Canada. The Chair confirmed acceptance of the terms of reference of the panel and the agenda for the meeting. Before the presentations commenced, the Chair briefly reviewed the process to be followed with respect to asking questions of the presenters.

Presentations

1. Health Portfolio Opioid Action Plan (Kirsten Mattison)

The presentation provided an overview of the Health Portfolio's Opioid Action Plan and provided information to support discussion on whether low-dose codeine products should require a prescription.

Issues raised by the panel, in questioning the presenter, included, but were not limited to:

The nature and magnitude of the problem that is trying to be resolved by making codeine a prescription drug.

The availability of data on codeine sales and use across Canada.

The experience of other regulators such as the Therapeutic Goods Administration in Australia and the province of Manitoba regarding codeine restrictions and utilization.

The presentation included a summary of the SAP-OUC's mandate and reviewed current opioid contraindications in Canadian and international labelling. The presentation concluded by reviewing the questions posed to the panel.

Issues raised by the panel, in questioning the presenter, included, but were not limited to:

The value of including morphine milligram equivalents (MME) in the product monographs for all opioid drugs.

The appropriate location for various types of information in the product monograph, e.g., in the Warnings and Precautions versus Contraindications section.

The presentation provided an update on the 2017 Canadian Guideline for Opioid Therapy and Chronic Non-Cancer Pain, summarizing the ten recommendations contained therein.

Issues raised by the panel, in questioning the presenter, included, but were not limited to:

When reviewing the opioid clinical literature, the need to take publication dates into account since methodologies and definitions may change over time.

The heterogeneity in the body of opioid clinical literature, due to differences in pain conditions and the use of concomitant non-opioid medications.

The decision criteria for increasing the dose of an opioid beyond the initial dose.

Lack of evidence of benefit in some sub-groups (i.e., heterogeneity of response).

Deliberations on the questions posed to panel (all panel members)

In addition to the above points, the discussion covered other areas, including:

The timeline for updating statements in product monographs.

Distinguishing between contraindications and warnings in product monographs.

The implications of using the MME, since the conversion factors for opioids are not precise or universally agreed upon numbers.

The need for prescribers to discuss with colleagues (i.e., co-health providers) before increasing the dose of an opioid for a given patient, and particularly if the dose would exceed 90 MME.

The appropriate duration of time to use an opioid in the management of acute pain.

The treatment of elderly patients who have used opioids for extended periods.

Tapering opioid doses for patients with chronic use.

The above list is by no means exhaustive and is intended only to give a sense of the type of issues discussed by the panel.

Final recommendations

(Note: Questions (in bold) posed by Health Canada, precede each set of recommendations)

Specific to the threshold dose:

Should a threshold dose (50 and/or 90 morphine milligram equivalents), as discussed in the recommendations of the new proposed Canadian guideline on the use of opioids for chronic non-cancer pain, be included in the Product Monograph (PM)?

Opioid dosing for chronic non-cancer pain: After a patient has been prescribed the appropriate low initial dose of an opioid, if it has not provided adequate pain management, the dose can be titrated up to an upper limit of 50 MME per day. Recognizing that aminorityofpatients may require a higher dose, the second ceiling dose would be 90 MME per day. As it is rarely justifiable to exceed 90 MME, in situations where physicians feel that it is necessary to prescribe > 90 MME per day this would be a situation of off-label prescribing conducted at the discretion of the treating physician. This information should be in the product monograph (PM) for all opioids. (Note: This would not apply to transdermal fentanyl as the initial dose already exceeds the 50 MME threshold, and subsequent doses will exceed 90 MME.)

Where should the information on the threshold dose be included in the PM (e.g. in the Warnings and Precautions or Dosing and Administration section)?

The information should be included in the Dosing and Administration section of the PM. The risks associated with doses above the 50 and 90 MME thresholds can be included in the Warning and Precautions.

Should the threshold dose information be emphasized by bolding it or placing it in a box?

It is recommended that the dosing threshold information be provide in a manner that would draw the prescriber's attention.

Do you think it should be specified that the threshold dose does not apply in end of life care, cancer pain and other similar situations, or is this self-evident?

It should be emphasized that the dosing threshold information only applies to chronic non-cancer pain.

Specific to the indication and clinical use:

Do you think the current indication for the extended/long-acting opioidsFootnote 1 is clearly worded and in line with the recommendations in the new guidance (i.e., opioids should not be considered as a first line treatment)? Should the indication be reworded to put more emphasis on the fact that opioids are not first line therapy?

Prior to using an extended/long acting opioid product, patients should have first tried a non-opioid pharmacological option, followed by a short acting opioid option.
[Product Name] is indicated for the management of pain:

severe enough to require daily, continuous therapy;

requiring long-term opioid treatment;

where the pain is opioid-responsive; and

where alternative options have been optimized and are inadequate.

[Product Name] is not indicated for the management of acute pain nor as an as-needed (prn) analgesic.

Do you think the indication for immediate release opioidsFootnote 2 should limit the duration of use (e.g. to 7 or 14 days), and consequently the amount of medicine that should be dispensed to patients?

Opioid prescriptions for the management for acute pain should be limited to 3 days duration. Recognizing that some patients may require a second course of therapy, either a repeat prescription x 1 or a 7 day prescription should be the maximum prescribed. The prescription should specify the maximum of tablets that can be used per day. This applies to opioid naïve patients only.

Should the PM include dosing instructions for stopping the opioid treatment after a few days to evaluate the need to continue treatment?

For acute pain management, the PM instructions for patients should include information to de-escalate their dose and to provide patients with permission to take less than the maximum daily dose.

Should a recommendation to consider tapering patients who are using chronic high doses of opioids be added to the PM?

Information providing encouragement and guidance (clear instructions) on how to taper patients using chronic high doses should be provided in the PM (as per current Canadian guidelines - see the end of the document). Information regarding the potential harms associated with excessively rapid reductions should also be disclosed. The goal for reduction should target the current threshold dose of 50 - 90 MME per day. Comparable information should also be included in the Patient Information Section (Part III of thePM).

Ready access to this information is felt to be critical to reducing chronic high dose opioid use as the barrier to prescribers undertaking this task are lack of knowledge, insufficient time, and poor motivation. Patient barriers include fear of withdrawal and inadequate alternatives.

Some studies have shown that opioids have marginal efficacy when used for chronic lower back pain. Should information from these published articles be added to the PM?

Discussing specific subgroups of pain disorders for which opioids might be prescribed should be avoided in the PM. Despite that average effects may be marginal for some conditions, a minority of patients will achieve a meaningful and long-term reduction in chronic pain. Evidence regarding specific disorders should be the domain of practice guidelines.

Specific to contraindications:

In addition to the current contraindications and in light of the draft guideline recommendations, should there be a contraindication or a relative contraindication for patients with:

A history of addiction?

An uncontrolled mental illness?

A Warning should be added regarding the use of opioids in patients with a history of any substance use disorder.

Is the contraindication on Labour, Delivery and Nursing Women compatible with the practice of medicine (i.e. use of opioids during labour and delivery)Footnote 3 and with the language used in the Warnings and PrecautionsFootnote 4?

Information advising against the use of opioids in Labour, Delivery and Nursing Women should be a Warning and not a Contraindication.

Are there any other contraindications, relative contraindications, or limitations in use that you feel are missing and should be added to the PM?

Warning: workplace (safety sensitive employment); sleep apnea.

Does the information in the PM provide prescribers and patients with adequate/sufficient information on the risks of opioids?

The PM should include a paragraph that explicitly lists the risks associated with the opioid use with respect to dose escalation and physical dependency. The information should discuss specific risks and try to provide some quantification of those risks.

There are situations where potential contraindications or limitations should perhaps not apply (e.g., trauma or cancer in a patient with previous addiction problems). Do you think that these situations are self-evident, or should they be described in the PM?

The information provided should be described as excluding active cancer treatment, palliative care, and end of life management.

Specific to low-dose codeine products:

Currently, low-dose codeine products are exempted from the Controlled Drugs and Substances Act (CDSA) and can be obtained without a prescription. Do you believe there would be merit in making these products prescription only, considering: the risks and benefits for patients, the impact it could have on patients and the health care system, etc.?

To address this issue much more information is required, e.g. more information on the demographics of the patients using these over-the-counter (OTC) products and whether these patients are also receiving other opioid products. In addition, the panel advises that no changes should be made until an evaluation of the consequences in Manitoba where new restrictions have been implemented. Information should be obtained regarding the outcomes that occurred in Australia where restrictions have been implemented. Outcomes of interest include whether there is an increase in the use of other opioids, the frequency of gastrointestinal bleeds (from non-steroidal anti-inflammatory drug use), and the frequency of acetaminophen toxicity.

Other items to consider:

PM isn't organized by dosing (acute vs. chronic pain)

Separate sections in PM for acute and chronic pain are not necessary. Where relevant, the information should always indicate whether it specifically applies to opioid use in the management of acute or chronic pain.

Closing remarks / Adjournment (Chair)

The Chair and Health Canada thanked the members for their participation. The meeting was adjourned.

[Note: This record of proceedings was submitted and approved in English by the Chair of the SAP-OUC.]

Guidelines for tapering chronic high dose opioid use:

A gradual dose reduction of 5-10% of the morphine equivalent dose every 2-4 weeks with frequent follow up is a reasonable rate of opioid tapering. Switching the patient from immediate release to controlled release opioids on a fixed dosing schedule may assist some patients in adhering to the withdrawal plan. Patients and physicians may wish to consult a pharmacist to assist with scheduling dose reductions.

Alternative methods of tapering include: (1) Reducing the dose rapidly over a few days/weeks or immediately. This method may result in severe withdrawal symptoms and is best carried out in a medically supervised withdrawal centre. (2) Tapering with methadone or buprenorphine-naloxone preparations. Patients may be rotated to methadone or buprenorphine-naloxone and then gradually tapered. In Canada, all physicians prescribing methadone require a Federal exemption for pain or addiction. The requirement for supplementary training for the use of buprenorphine-naloxone varies from province to province. If unfamiliar, clinicians should consult with someone knowledgeable with buprenorphine-naloxone use.

In patients struggling with the tapering plan (distressing or intolerable pain/withdrawal symptoms/decreased function which persists longer than 4 weeks), pausing the taper and re-evaluating the patient's pain/clinical status/coping mechanisms and the approach to tapering can help formulate a go-forward plan. In patients with the emergence of significant mental health symptoms and/or ambiguous drug-related behaviours, consultation with local experts is advised. Patients should be encouraged to taper to the lowest opioid dose achievable without a loss of previously achieved function. Some patients may not eliminate use of opioids, but any reduction in dose may be beneficial.

Footnotes

Footnote 1

[Product Name] is indicated for the management of pain severe enough to require daily, continuous, long-term opioid treatment, and:where the pain is opioid-responsive; andwhere alternative options are inadequate.[Product Name] is not indicated as an as-needed (prn) analgesic.

Labour, Delivery and Nursing Women: Since opioids can cross the placental barrier and are excreted in breast milk, Brand Name should not be used unless, in the judgement of the physician, the potential benefits outweigh the risks. Respiratory depression can occur in the infant if opioids